As an MD/PhD student, my goal is to work at the interface of basic research and clinical medicine. I am fascinated by the molecular controls of cellular responses to environmental events, such as infection by a pathogen or damage from an exogenous source. Understanding these responses may lead to new therapies for a variety of diseases. The GI tract and liver are intriguing systems as they are constantly exposed to a variety of pathogens. The clinical discipline of gastroenterology is fascinating and has many areas open to investigation. I envision myself as primarily a research scientist at an academic medical center, but with the added benefit of learning from my patients and perhaps translate my experiments to treatments. The proposed project and training plan will provide me training in hypothesis-driven research design and interpretation. Herpes simplex virus 1 (HSV-1) is a ubiquitous pathogen that causes a wide range of human disease, including such well-known conditions as cold sores, keratoconjunctivitis, and encephalitis. HSV-1 has an expanded spectrum of pathologies in immunocompromised patients (e.g. organ transplant recipients and AIDS and cancer patients) who often experience gastrointestinal (GI) manifestations of this virus. While HSV-1 is able to invade most mucocutaneous surfaces, the most common GI site of infection is the esophagus, where HSV-1 frequently causes recurrent epithelial ulceration. The estimates of the incidence of herpes esophagitis vary widely, with some studies reporting as much as 15% of transplant recipients testing positive. Herpes esophagitis usually presents as a reactivation from latency in the nodose ganglion of the vagus nerve. Despite the significance of this clinical problem, research toward understanding the molecular mechanisms of virus- host interactions in esophageal epithelial remains inadequate. HSV-1 interacts with host cells on the molecular level, presumably to optimize its environment for the specific phase of its lifecycle. One of the pathways activated by HSV-1 is the DNA damage response (DDR), initiated by the phosphorylation of a sensor kinase ataxia telangiectasia mutated (ATM). Activated ATM and other DDR components co-localize to the viral replication compartments during lytic infection. Furthermore, in neurons, which lack nuclear ATM and Chk2 and are incapable of mounting a DDR, HSV-1 infection is typically latent. In preliminary studies in corneal and esophageal cells, we have found that inhibition of ATM or the downstream Chk2 kinase leads to greatly reduced viral replication,. Based on these observations, we hypothesize that activation of ATM and the DDR by HSV-1 is a switch to allow for productive infection. The goal of this proposal is to utilize in vitro and in vivo experiments to identify the mechanism by which HSV-1 activates ATM in esophageal epithelial cells and to elucidate the role of DDR in the lifecycle of HSV-1. These studies will impact our understanding of the molecular pathways underlying HSV-1 infection and reactivation from latency, potentially identifying novel therapeutic targets for the treatment of herpes esophagitis.